Advancing age is the primary non-modifiable risk factor for cardiovascular diseases (CVD), such as atherosclerosis, and arterial dysfunction is an important contributor to this increased disease risk. The proposed studies will explore the novel hypothesis that an age-associated reduction in microRNA, miR-92a and its cluster miR-17-92, underlie age-associated arterial dysfunction and accelerated atherosclerotic disease progression. Because obesity is epidemic in US adults and is often a co-morbidity of older age, we will study both normal chow and high fat fed young and old mice to determine if aging per se exaggerates the negative influence of diet-induced obesity on vascular function and disease and if this is mediated by further decreases in arterial miR-92. We will utilize the well-established B6D2F1 mouse model of vascular aging and manipulate miR-92 by in vivo treatment with inhibitor and mimic oligomers as well as utilize genetic models to both up - and down-regulate miR-17-92, in the endothelium and whole body; respectively. We will assess measures of arterial function, such as endothelium dependent dilation, angiogenesis and large artery stiffening as well as assess atherosclerotic disease progression using a surgical model of disturbed carotid artery blood flow in mice crossed into an athero-prone background. Using targeted and unbiased approaches, we will explore the downstream targets of miR-92a/miR-17-92 and how these impact arterial function and disease. Last, using in vitro cell and tissue culture models we will determine upstream modulators of miR-17-92 expression, including regulation by the transcription factors c-myc and p53, as well as the role of altered shear stress in the regulation of miR-17-92 expression. The results will elucidate a novel mechanism underlying age-associated vascular dysfunction and disease risk and will provide critical evidence for a novel therapeutic target that may be effective in the treatment of CVD in older adults.